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J R Soc Med. 2006 June; 99(6): 273–274.
PMCID: PMC1472720

Complicity theory: an explanation for the `coxib problem'?

The `coxib' controversy continues to rage. In addition to articles in this and other journals,1,2 there are ongoing lawsuits and continuing media coverage. In this month's journal we hear of more inconsistencies in the reporting of adverse events in trials of celecoxib.3

The basic coxib idea is a good one. Non-steroidal anti-inflammatory drugs (NSAIDs), which work by inhibition of cyclooxygenase(COX), are valuable drugs for people with inflammatory disorders. We know that there are two COX enzymes that are involved in inflammation, and that only one of them protects the gastrointestinal tract. So it makes sense to look for selective inhibitors that might have anti-inflammatory and analgesic properties, without causing gastrointestinal problems. And the idea works, perhaps even better than we expected, as some of the coxibs—COX-2 inhibitors—seem to have superior analgesic properties to their COX-1 inhibiting ancestors (the traditional NSAIDs), and they do seem to cause less gastrointestinal problems.4 The problem, as just about everyone in the world now knows, is that coxibs come with the price of an increase in cardiovascular adverse events. This should not have come as a surprise. The possibility of an increased risk was known about long before the now infamous CLASS and VIGOR studies,5,6 as it was a theoretical complication of COX-2 inhibition highlighted by Fitzgerald's group and others in the 1990s.7

The increase in cardiovascular adverse events with coxib use may not be as big a problem as has been suggested. Clearly there is an increased risk of myocardial infarction in those who take some coxibs.1 But the risk is not huge, and the numbers of events caused relatively small. Furthermore, if we were to avoid using them in those with other risk factors for cardiovascular disease, the increase in absolute risk for any given individual would probably be marginal. It is hard to balance the risk of a fatal adverse event in a few, against major symptomatic benefit in the majority, 8 but many of our patients would clearly opt for the symptomatic relief. So, the logical strategy for those who need an anti-inflammatory agent is to use coxibs in those who have risk factors for gastrointestinal problems and a traditional NSAID for this with cardiovascular risk factors. But most of us are not doing that. First, we have allowed the long-standing rhetoric surrounding all NSAIDs to convince us to use them for any sort of painful problem, whether inflammation exists or not—so the indications for their use have expanded.9 Second, a series of scandals surrounding all types of NSAID have altered our perceptions and behaviours. The public have now lost confidence and the professionals are confused. Some are pursuing the `wicked' pharmaceutical industry, many are nervous of coxibs, and some are giving up using NSAIDs altogether.

There are generally two schools of thought on how we get into a mess of this sort: the conspiracy theory and the cock-up theory. I generally believe in cock-up rather than conspiracy. But in this case there has been much talk about conspiracy and cover-ups within the industry. One can see why. The potential profits that can come from a good anti-inflammatory drug are enormous, and it is sometimes hard to believe that any drug company would not be `influenced' by the prospect of those profits. And I think their marketing divisions have been. The money and expertise that went into the launches of celecoxib and rofecoxib was truly obscene. The more serious accusation is that the science done by and for the industry has also been biased and corrupted by these financial interests. Maybe it has, but little direct evidence has emerged to support such accusations. In this instance, I believe the main problem belongs within the province of a third `how-to-get-into-a-mess-like-this-one' theory—complicity theory.10

Complicity works like this. All those with a vested interest in an enterprise get sucked into the rhetoric associated with it, and they soon `believe' in everything that is going on within that enterprise. If personal financial gain is involved, corruption may also occur. So, in the case of drugs such as anti-inflammatory agents, researchers and prescribers work with the industry to promote the development, testing and use of these drugs. Personal financial gains come through company shares, consultancies and free trips to exotic locations (for those who do research or actively promote the drugs), trips to educational meetings (for specialists), or `just' free lunches (for just about everybody—does any doctor still buy his/her own lunch?).11 If this goes on for long enough (and it has), everyone starts to believe that they are doing the right thing when they accept company largesse, and to believe in the drugs. And they do not realize that their ability to look at data critically, and at drug use objectively, has been compromised. So, when data comes along that says that rofecoxib causes heart attacks, lots of people say `wait a minute, rofecoxib is wonderful, so maybe the explanation for this is that the NSAID comparator (naproxen) is also a wonder drug and is protecting people against heart attacks'.12 The marketing pressures make all of this worse, of course. So when a paper gets published that says that celecoxib is wonderful, it gets distributed to everyone (as they attend the free lunch event). And when it turns out that the data are flawed (fraud?) the papers still go on being distributed to everyone.13

The pharmaceutical industry has developed a position of extraordinary power over governments, medical research and medical practice.14,15 But complicity theory makes it clear that this would not have been possible without others going along with their story. Doctors have been terrible in that regard; we now work in an industry where companies who stand to profit from our activities sponsor most of our postgraduate education. Politicians are also to blame. For example, Gordon Brown is campaigning to keep the pharmaceutical industry in Britain, to help `UK plc', and one result of that is that all of us (including Medical Research Council scientists like myself), are being encouraged to work with the industry.

The complicity of politicians and health professionals with the pharmaceutical industry agenda, driven by the profit motive, has made us all blind to data and to common sense. For example, there is now widespread use of drugs (including NSAIDs and coxibs) for problems that are largely social, behavioural or mechanical in origin and the prevention and treatment of which is more logically approached through behavioural interventions than by the use of drugs.16 Most current medical research, as well as medical practice, is dominated by the vested interests of the multi-national pharmaceutical industry, which is now busy inventing diseases for which it can find drugs.17 We now live in a medical culture that appears to have become completely drug dependent—because of money. How bad is that?

Notes

Acknowledgments I should like to thank Jonathan Sterne for help and advice when preparing this piece.

Competing interests None

References

1. Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R. Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis. J R Soc Med 2006;99: 132-40 [PMC free article] [PubMed]
2. Curfman G, Morrissey S, Drazen J. Expression of Concern Reaffirmed. N Engl J Med 2006;354: 1193. [PubMed]
3. Weatherall M, Aldington S, Caldwell B, Beasley R. Inconsistencies in cardiovascular data from COX-2 inhibitor trials—is it a CLASS effect? J R Soc Med 2006;99: 275-6 [PMC free article] [PubMed]
4. Hawkey C, Langman M. Non-steroidal anti-inflammatory drugs: overall riks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors. Gut 2003;52: 600-8 [PMC free article] [PubMed]
5. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study. JAMA 2000;284: 1247-55 [PubMed]
6. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity with rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR study group. N Engl J Med 2000;343: 1520-8 [PubMed]
7. McAdam B, Catella-Lawson F, Mardini I, Kapoor S, Lawson J, Fizgerald G. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Nat Acad Sci 1999;96: 272-7 [PubMed]
8. Dieppe P, Bartlett C, Davey P, Doyal L, Ebrahim S. Balancing benefits and harms: the example of non-steroidal anti-inflammatory drugs. BMJ 2004;329: 31-4 [PMC free article] [PubMed]
9. Dieppe P, Ebrahim S, Martin R, Juni P. Lessons from the withdrawal of rofecoxib. BMJ 2004;329: 867-8 [PMC free article] [PubMed]
10. Kline A. On complicity theory. Sci Eng Ethics 2006;12: 257-64 [PubMed]
12. Watson D, Rhodes T, Cai B, Guess H. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002;162: 1105-10 [PubMed]
13. Juni P, Rutjs AW, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ 2002;324: 1287-8 [PMC free article] [PubMed]
14. Angell M. The Truth About The Drug Companies: How They Deceive Us and What To Do About It. London: Random House, 2005
15. Weber L. Profits Before People?: Ethical Standards and The Marketing and Prescription of Drugs. Indiana: Indiana University Press, 2006
16. Marteau T, Dieppe P, Foy R, Kinmonth AL, Schneiderman N. Behavioural medicine: changing our behaviour. BMJ 2006;332: 437-8 [PMC free article] [PubMed]
17. Moynihan R, Cassels A. Selling Sickness: How The World's Biggest Pharmaceutical Companies Are Turning Us All Into Patients. California: Avalon Publishing Group, 2005

Articles from Journal of the Royal Society of Medicine are provided here courtesy of Royal Society of Medicine Press